Science and Scientists on the Vineyard

Gene editing Lyme-fighting mice and beyond.

MIT professor Kevin Esvelt in his lab researching ways to combat Lyme disease by gene editing mice. MIT Media Lab

Paul Levine, a resident of West Tisbury who was a professor at Harvard and visiting professor at Stanford University, will contribute this occasional column devoted to scientific research taking place today, along with profiles of the Island’s scientists and their work and facts of scientific note on the Island. This week, he discusses the genetics research that has led to CRISPR, which stands for “Clustered Regularly Interspaced Short Palindromic Repeats.” If you’re wondering what that is, read on.

“Science and Scientists on the Vineyard” returns this month with a two-part column on the subject that also goes by such names as genetic engineering, gene therapy, genetic modification, and recently gene editing. Regardless of its name, the technology has from its outset been lauded but also seen as controversial. CRISPR is in the news almost weekly because of questions of the ethics of its application and its potential to do both good and bad.

Over the past two years CRISPR has garnered a great deal of public notice through articles in scientific journals such as Science and Nature, major newspapers such as the New York Times, and in magazines like Time and the New Yorker. It has also been the subject on the radio of WCAI’s “Living Lab” and NPR’s “Science Friday.”

Last summer, The MV Times reported on the CRISPR technique being used to produce Borrelia-resistant white-footed mice to control Lyme disease both here and on Nantucket (July 20, “Scientist proposes genetic attack on Martha’s Vineyard ticks”).

The impact that CRISPR will have on the future of genetic engineering and gene therapy is at once scientifically, ethically, politically, and economically immense. Let’s go back to the early days of plant and animal breeding, and from there to the era of the production of genetically modified foods, and finally to the early efforts of human gene therapy, to put the subject into a historical context that I hope will provide for a rational discussion of the effects that CRISPR might have on human society.

First, put aside whatever opinions you may have for or against genetically modified organisms (including humans), and look at the history behind the genetic manipulation of plants and animals that has brought us to where we are today. Domestication and breeding of plants and animals may go back at least 11,000 years, with practices of selective breeding that led to improved survival, yield, and quality of domesticated plants, and overcame the deleterious effects of inbreeding.

After the 1905 rediscovery of Mendel’s Laws of Inheritance, a scientific approach to the development of methods of plant and animal breeding followed rapidly. In 1908, the plant geneticist George Shull at the Cold Spring Laboratory on Long Island showed that when he crossed inbred lines of corn that had deteriorated (showing lower yields, vigor, and disease resistance), the hybrids, sharing the genes of the inbred parents, completely recovered. Their yields were much greater than the inbred lines from which they were derived. A year later, Shull published the procedures for hybridization that became standard for corn and other organisms.

Hybridization of inbred lines of plants and animals means mingling the genes of the parents. But what if the desire is to focus on one specific gene? For example, what if one were to insert one of the flavor genes of an heirloom tomato into the DNA of a commercial variety, or to engineer human stem cells with normal genes to cure genetic disorders such as cystic fibrosis, sickle cell anemia, and Tay-Sachs disease?

In 1972, Stanford biochemist Paul Berg showed how a foreign gene could be isolated and inserted into the genome of E. coli, the common human gut bacterium, to produce a RecDNA (recombinant DNA) organism. In 1974, Stanley Cohn at Stanford University and Herbert Boyer of the University of California, San Francisco, and their colleagues introduced genes from the toad Xenopus laevis into E. coli bacteria.

Even before Mr. Berg published his seminal paper on recDNA, he became aware that there was the question of a possible health threat of combining genes from different organisms in the common E. coli. Was it possible that some virulent strain would emerge because of its recombinant genome?

Mr. Berg’s recognition of this possibility, and the concerns of some of his colleagues, led them in 1974 to write a letter to others engaged in recDNA research to urge them to impose a moratorium on certain types of experiments that might be hazardous. There followed a conference of scientists in 1975 at the Asilomar Conference Center in Pacific Grove, Calif., to address the risks of the research. This meeting led to others, not only of concerned scientists but of ethicists, politicians, and members of the public.

In 1975 the National Institutes of Health produced a set of guidelines for recombinant DNA research. In a number of instances, concern over the possible hazards of recombinant DNA research and the need to carefully monitor that research became a local and state issue. In June 1976, the Cambridge City Council met to take up the question of Harvard University’s plan to build and operate a special laboratory for the research. The city council discussed the possibility of the research becoming a health hazard to inhabitants of their city. After a contentious debate between members of the council and Harvard scientists, the council appointed a Cambridge Experimental Review Board, and ultimately a Cambridge Biohazards Committee, out of which came recommendations for oversight of the research. Similar concerns were expressed by the New York State Environmental Protection Division, and by the city of San Diego in California. The history of the controversy is excellently set forth in the book “The Recombinant DNA Debate” by David A. Jackson and Stephen P. Stich.

Thus began the era of recombinant DNA genetic engineering that saw the insertion of genes into bacteria and yeast for the production of insulin, some growth hormones, blood clotting factors, and vaccines.

Recombinant DNA technology also began to be applied to the production of genetically modified plants and animals, and thus the availability of genetically modified foods.

Since those days, products produced by genetic manipulation by the pharmaceutical, agricultural, and food industries have grown immensely. So have the number of questions regarding their safety, questions for which there is no universal answer, and so discussions both pro and con continue to this day. A study of both positions can be found on the Web in articles here:

Today, with the advent of CRISPR, we find scientists and the public in positions not unlike those of the early days of recombinant DNA research, but with far greater intensity: The power of CRISPR for genetic engineering far exceeds that of the recombinant DNA technique. The next time I write on the subject, I will undertake to describe CRISPR gene editing, the larger-than-life characters at the center of the research, some of the current applications of CRISPR, and some research projects that focus on human gene editing, along with the ethical questions that have arisen as a consequence.